Benzophenone-2-carboxylic acid addition salts of 1-methyl-3-(di-2-thienylmethylene) pperidine



United States Patent Office 3,145,212 Patented Aug. 18, 1964 3,145,212 BENZOPHENONE-Z-CARBOXYLIC ACID ADDI- TION SALTS OF 1-METHYL-3-(DI-2-THIEN- YLMETHYLENE) PIPERIDINE Makoto Yamamoto, Yao, and Hiroshi Yoshikawa, Toyonaka, Japan, assignors to Tanabe Seiyaku Co., Ltd., Higashi-ku, Osaka, Japan No Drawing. Filed Dec. 4, 1961, Ser. No. 156,940 Claims priority, application Japan Dec. 19, 1960 2 Claims. (Cl. 260-293.4)

This invention relates to benzophenone-Z-carboxylic acid addition salts of 1-methyl-3-(di-Z-thienylmethylene) piperidine and to processes for preparing the same.

It has been known that the acid addition salts of lmethyl-3-(di-Z-thienylmethylene)piperidine are effective with human beings as an antitussive and an expectorant composition (Kase et al., Chemical and Pharmaceutical- Bulletin, Vol. 7, page 372, 1959; Sugimoto et al., ibid., Vol. 8, page 745, 1960). However, the water-soluble acid addition salts of the above compound, such as the hydrochloride and the citrate, are inconvenient for oral administration due to their bitter taste.

According to this invention we have now found that certain benzophenone-Z-carboxylic acid addition salts of l-methyl-3-(di-Z-thienylmethylene)piperidine are palata-i ble and are useful in therapeutics especially for oral administration.

The new compounds of this invention are represented by the following formula:

wherein R stands for H atom or OH radical.

The new compounds are advantageously prepared by metathetically reacting, for instance, an alkali metal salt of benzophenone-Z-carboxylic acid or its 4'-hydroxy derivative with a water-soluble acid addition salt of the base, such as the hydrochloride and the citrate, in an aqueous solution. After standing for a time, the sparingly soluble addition salts crystallize out. However, it is also possible to react the free base directly with the carboxylic acid. In this case, the reaction is advantageously carried out in an organic solvent, such as ether or acetone, from which the desired salts are obtained by conventional means.

The following examples illustrate the invention.

Example 1 16.5 g. of l-methyl-3-(di-2-thienylmethylene)piperidine. base in 40 ml. of acetone was added to a solution of 14.5 g. of 4-hydroxybenzophenone-Z-carboxylic acid in 70 ml. of acetone with stirring.

Crystallization began immediately. The crystals were recovered by filtration, washed with a small amount of acetone and dried. 30 g. of 4-hydroxybenzophenone-2- carboxylic acid addition salt of 1-methyl-3-(di-Z-thienylmethylene)piperidine melting at 187-190 C. was obtained.

Yield: 96.7% of theory.

The base contenL-Calculated, 53.2%. Found, 51.8%.

Example 2 Yield: of theory.

Example 3 2.7 g. of l-methyl-3-(di-2-thienylmethylene)piperidine in 40 ml. of acetone was added to a solution of 2.4 g. of benzophenone-Z-carboxylic acid hydrate in 5 ml. of acetone. The mixture was allowed to stand for a time at room temperature thereby the addition salt crystallized out. The crystals were recovered by filtration, washed with acetone and dried. 4.3 g. of benzophenone-Z-carboxylic acid addition salt of l-methyl-3-(di-Z-thienylmethylene)piperidine melting at 132 C. was obtained.

Yield: 87.4% of theory.

The base c0ntent.-Calculated, 54.9%. Found, 54.4%.

Example 4 Yield: 85.5% of theory.

What we claim is:

1. The benzophenone-Z-carboxylic acid addition salt of 1-methyl-3-(di-Z-thienylmethylene)piperidine.

2. The 4-hydroxybenzophenone-2-carboxylic acid addition salt of 1-methyl-3-(diQ-thienylmethylene)piperidine.

References Cited in the file of this patent UNITED STATES PATENTS Stehman et a1 Apr. 1, 1958 Elpern July 10, 1962 OTHER REFERENCES Prigot et al.: Journal of the American Chemical Society, Volume 70, pages 2758-2759 (1948).

Higaki et al.: Yakugaku Kenkyu, Volume 21, page 7 (1959), 260-2934.

Sugimoto et al.: Chemical and Pharmaceutical Bulletin, Volume 8, pages 745-748 (1960). 

1. THE BENZOPHENONE-2-CARBOXYLIC ACID ADDITION SALT OF 1-METHYL-3-(DI-2-THIENYLMETHYLENE)PIEPERIDINE. 